Induction of type I and III interferons by viral and endogenous stimuli in systemic sclerosis

The interferon (IFN) system is activated in systemic sclerosis (SSc), and various stimuli may induce IFN in SSc patients. We investigated whether type I and III IFN responses to Toll-like receptor (TLR)-7/8/9 stimulation differ between patients with SSc and healthy individuals, and whether IFN production is associated with clinical features.

Peripheral blood mononuclear cells (PBMCs), monocyte-depleted PBMCs, and monocytes were prepared from 45 SSc patients and 47 healthy controls. Cells were stimulated with RNA-containing immune complexes (RNA-IC), an RNA oligonucleotide (ORN8L), or inactivated herpes simplex virus (HSV) targeting TLR7, TLR8, and TLR9, respectively. IFN-α, -β, -λ₁, and -λ₂ levels were measured by immunoassays, and intracellular IFN-α by flow cytometry.

SSc PBMCs produced type I and III IFNs in response to all three stimuli, with the strongest response following TLR9 activation. Compared with controls, SSc PBMCs produced less IFN-α (p < 0.02), whereas IFN-β levels were higher in SSc monocytes (342 vs 59.9 pg/mL, p = 0.041) when activated via TLR9. IFN-λ_1/2 levels were consistently lower than type I IFNs. IFN-α priming increased TLR7/8-induced IFN production in PBMCs. Strong TLR9-mediated IFN-α production was associated with diffuse cutaneous SSc, anti-RNA-polymerase III autoantibodies, and interstitial lung disease (ILD).

Leucocytes from SSc patients produce type I and III IFNs in response to a broad range of TLR stimuli. IFN-α priming enhanced TLR7/8-induced IFN production, suggesting that strong IFN inducers, e.g. certain viruses, may amplify IFN synthesis in response to endogenous TLR ligands and contribute to SSc pathogenesis, including the development of ILD.